Signaling molecules in nonfamilial pulmonary hypertension

Lingling Du, Christopher C. Sullivan, Danny Chu, Augüstine J. Cho, Masakuni Kido, Paul L. Wolf, Jason Yuan, Reena Deutsch, Stuart W. Jamieson, Patricia A. Thistlethwaite

Research output: Contribution to journalArticle

302 Citations (Scopus)

Abstract

BACKGROUND: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPK2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. RESULTS: The expression of angiopoietin-1 messenger RNA and the protein itselfand the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)500-509
Number of pages10
JournalNew England Journal of Medicine
Volume348
Issue number6
DOIs
StatePublished - Feb 6 2003
Externally publishedYes

Fingerprint

Angiopoietin-1
Pulmonary Hypertension
Bone Morphogenetic Protein Receptors
Lung
Type II Bone Morphogenetic Protein Receptors
Endothelial Cells
Proteins
Smooth Muscle Myocytes
Smooth Muscle
Blood Vessels
Molecular Biology
Phosphorylation
Biopsy
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Du, L., Sullivan, C. C., Chu, D., Cho, A. J., Kido, M., Wolf, P. L., ... Thistlethwaite, P. A. (2003). Signaling molecules in nonfamilial pulmonary hypertension. New England Journal of Medicine, 348(6), 500-509. https://doi.org/10.1056/NEJMoa021650

Signaling molecules in nonfamilial pulmonary hypertension. / Du, Lingling; Sullivan, Christopher C.; Chu, Danny; Cho, Augüstine J.; Kido, Masakuni; Wolf, Paul L.; Yuan, Jason; Deutsch, Reena; Jamieson, Stuart W.; Thistlethwaite, Patricia A.

In: New England Journal of Medicine, Vol. 348, No. 6, 06.02.2003, p. 500-509.

Research output: Contribution to journalArticle

Du, L, Sullivan, CC, Chu, D, Cho, AJ, Kido, M, Wolf, PL, Yuan, J, Deutsch, R, Jamieson, SW & Thistlethwaite, PA 2003, 'Signaling molecules in nonfamilial pulmonary hypertension', New England Journal of Medicine, vol. 348, no. 6, pp. 500-509. https://doi.org/10.1056/NEJMoa021650
Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL et al. Signaling molecules in nonfamilial pulmonary hypertension. New England Journal of Medicine. 2003 Feb 6;348(6):500-509. https://doi.org/10.1056/NEJMoa021650
Du, Lingling ; Sullivan, Christopher C. ; Chu, Danny ; Cho, Augüstine J. ; Kido, Masakuni ; Wolf, Paul L. ; Yuan, Jason ; Deutsch, Reena ; Jamieson, Stuart W. ; Thistlethwaite, Patricia A. / Signaling molecules in nonfamilial pulmonary hypertension. In: New England Journal of Medicine. 2003 ; Vol. 348, No. 6. pp. 500-509.
@article{c04c8534d8044dd585d70a4e019b8d0d,
title = "Signaling molecules in nonfamilial pulmonary hypertension",
abstract = "BACKGROUND: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPK2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. RESULTS: The expression of angiopoietin-1 messenger RNA and the protein itselfand the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.",
author = "Lingling Du and Sullivan, {Christopher C.} and Danny Chu and Cho, {Aug{\"u}stine J.} and Masakuni Kido and Wolf, {Paul L.} and Jason Yuan and Reena Deutsch and Jamieson, {Stuart W.} and Thistlethwaite, {Patricia A.}",
year = "2003",
month = "2",
day = "6",
doi = "10.1056/NEJMoa021650",
language = "English (US)",
volume = "348",
pages = "500--509",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "6",

}

TY - JOUR

T1 - Signaling molecules in nonfamilial pulmonary hypertension

AU - Du, Lingling

AU - Sullivan, Christopher C.

AU - Chu, Danny

AU - Cho, Augüstine J.

AU - Kido, Masakuni

AU - Wolf, Paul L.

AU - Yuan, Jason

AU - Deutsch, Reena

AU - Jamieson, Stuart W.

AU - Thistlethwaite, Patricia A.

PY - 2003/2/6

Y1 - 2003/2/6

N2 - BACKGROUND: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPK2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. RESULTS: The expression of angiopoietin-1 messenger RNA and the protein itselfand the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.

AB - BACKGROUND: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPK2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. RESULTS: The expression of angiopoietin-1 messenger RNA and the protein itselfand the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.

UR - http://www.scopus.com/inward/record.url?scp=0037421604&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037421604&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa021650

DO - 10.1056/NEJMoa021650

M3 - Article

C2 - 12571257

AN - SCOPUS:0037421604

VL - 348

SP - 500

EP - 509

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 6

ER -